Mucosal addressin cell adhesion molecule (MAdCAM) is a member of the immunoglobulin superfamily of cell adhesion receptors. The selectivity of lymphocyte homing to specialized lymphoid tissue and mucosal sites of the gastrointestinal tract is determined by the endothelial expression of MAdCAM (Berlin, C. et al., Cell, 80:413-422(1994); Berlin, C., et al., Cell, 74:185-195 (1993); and Erle, D. J., et al., J. Immunol., 153: 517-528 (1994)). MAdCAM is uniquely expressed on the cell surface of high endothelial venules of organized intestinal lymphoid tissue, such as Peyer's patches and mesenteric lymph nodes (Streeter et al., Nature, 331:41-6 (1988); Nakache et al., Nature, 337:179-81 (1989); Briskin et al., Am. J. Pathol. 151-97-110 (1997)), but also in other lymphoid organs, such as pancreas, gall bladder and splenic venules and marginal sinus of the splenic white pulp (Briskin et al(1997), supra; Kraal et al., Am. J. Path., 147: 763-771 (1995)).
While MAdCAM plays a physiological role in gut immune surveillance, it appears to facilitate excessive lymphocyte extravasation in inflammatory bowel disease under conditions of chronic gastrointestinal tract inflammation. TNFα and other pro-inflammatory cytokines increase endothelial MAdCAM expression and, in biopsy specimens taken from patients with Crohn's disease and ulcerative colitis, there is an approximate 2-3 fold focal increase in MAdCAM expression at sites of inflammation (Briskin et al. (1997), Souza et al., Gut, 45:856-63 (1999); Arihiro et al., Pathol Int., 52:367-74 (2002)). Similar patterns of elevated expression have been observed in experimental models of colitis (Hesterberg et al., Gastroenterology, 111: 1373-1380 (1997); Picarella et al., J. Immunol., 158: 2099-2106 (1997); Connor et al., J Leukoc Biol., 65:349-55 (1999); Kato et al. , J Pharmacol Exp Ther., 295:183-9 (2000); Hokari et al. , Clin Exp Immunol., 26:259-65 (2001); Shigematsu et al., Am J Physiol Gastrointest Liver Physiol., 281:G1309-15 (2001)). In other pre-clinical models for inflammatory conditions, such as insulin-dependent diabetes (Yang et al. Diabetes, 46:1542-7 (1997); Hänninen et al., J Immunol., 160:6018-25 (1998)), graft versus host disease (Fujisaki et al., Scand J Gastroenterol., 38:437-42 (2003), Murai et al. , Nat Immunol., 4:154-60 (2003)), chronic liver disease (Hillan et al., Liver, 19:509-18 (1999); Grant et al., Hepatology, 33:1065-72 (2001)), inflammatory encephalopathy (Stalder et al., Am J Pathol., 153:767-83 (1998); Kanawar et al., Immunol Cell Biol., 78:641-5 (2000)), and gastritis (Barrett et al. , J Leukoc Biol., 67:169-73 (2000); Hatanaka et al., Clin Exp Immunol., 130:183-9 (2002)), there is also reawakening of fetal MAdCAM expression and participation of activated α4β7+ lymphocytes in disease pathogenesis. In these inflammatory models as well as hapten-mediated (e.g., TNBS, DSS, etc.) or adoptive transfer (CD4+CD45Rbhigh) mouse colitic models, the rat anti-mouse MAdCAM monoclonal antibody (mAb), MECA-367, which blocks the binding of α4β7+ lymphocytes to MAdCAM, reduces the lymphocyte recruitment, tissue extravasation, inflammation and disease severity. Mouse monoclonal antibodies (mAbs) against human MAdCAM also have been reported (see, e.g., WO 96/24673 and WO 99/58573).
Given the role of MAdCAM in inflammatory bowel disease (IBD) and other inflammatory diseases associated with the gastrointestinal tract or other tissues, a means for inhibiting α4β7 binding and MAdCAM-mediated leukocyte recruitment is desirable. It further would be desirable to have such therapeutic means with advantageous properties including but not limited to the absence of unwanted interactions with other medications in patients and favorable physico-chemical properties such as pK/pD values in humans, solubility, stability, shelf-life and in vivo half-life. A therapeutic protein, such as an antibody, would advantageously be free of unwanted post-translational modifications or aggregate formation. Accordingly, there is a critical need for therapeutic anti-MAdCAM antibodies.